CONTEXT: The personality trait of conscientiousness has been related to morbidity and mortality in old age, but its association with the development of Alzheimer disease is not known. OBJECTIVE: To test the hypothesis that a higher level of conscientiousness is associated with decreased risk of Alzheimer disease. DESIGN: Longitudinal clinicopathologic cohort study with up to 12 years of annual follow-up. SETTING: The Religious Orders Study. PARTICIPANTS: A total of 997 older Catholic nuns, priests, and brothers without dementia at enrollment, recruited from more than 40 groups across the United States. At baseline, they completed a standard 12-item measure of conscientiousness. Those who died underwent a uniform neuropathologic evaluation from which previously established measures of amyloid burden, tangle density, Lewy bodies, and chronic cerebral infarction were derived. MAIN OUTCOME MEASURES: Clinical diagnosis of Alzheimer disease and change in previously established measures of global cognition and specific cognitive functions. RESULTS: Conscientiousness scores ranged from 11 to 47 (mean, 34.0; SD, 5.0). During follow-up, 176 people developed Alzheimer disease. In a proportional hazards regression model adjusted for age, sex, and education, a high conscientiousness score (90th percentile) was associated with an 89% reduction in risk of Alzheimer disease compared with a low score (10th percentile). Results were not substantially changed by controlling for other personality traits, activity patterns, vascular conditions, or other risk factors. Conscientiousness was also associated with decreased incidence of mild cognitive impairment and reduced cognitive decline. In those who died and underwent brain autopsy, conscientiousness was unrelated to neuropathologic measures, but it modified the association of neurofibrillary pathologic changes and cerebral infarction with cognition proximate to death. CONCLUSION: Level of conscientiousness is a risk factor for Alzheimer disease.